Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach

ABSTRACT

Methods and apparatus are provided for pulsed electric field neuromodulation via an intra-to-extravascular approach, e.g., to effectuate irreversible electroporation or electrofusion, necrosis and/or inducement of apoptosis, alteration of gene expression, changes in cytokine upregulation and other conditions in target neural fibers. In some embodiments, the ITEV PEF system comprises an intravascular catheter having one or more electrodes configured for intra-to-extravascular placement across a wall of patient&#39;s vessel into proximity with target neural fibers. With the electrode(s) passing from an intravascular position to an extravascular position prior to delivery of the PEF, a magnitude of applied voltage or energy delivered via the electrode(s) and necessary to achieve desired neuromodulation may be reduced relative to an intravascular PEF system having one or more electrodes positioned solely intravascularly. The methods and apparatus of the present invention may, for example, be used to modulate one or more target neural fibers that contribute to renal function.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 12/616,708, filed Nov. 11, 2009, now U.S. Pat. No. 7,873,417,which is a continuation of U.S. patent application Ser. No. 11/363,867,filed Feb. 27, 2006, now U.S. Pat. No. 7,620,451, which claims thebenefit of U.S. Provisional Application No. 60/813,589, filed on Dec.29, 2005, the disclosures of which are incorporated herein by referencein their entirety.

U.S. patent application Ser. No. 11/363,867, now U.S. Pat. No.7,620,451, is also a continuation-in-part of each of the followingco-pending U.S. Patent Applications:

(a) U.S. patent application Ser. No. 11/129,765, filed on May 13, 2005,now U.S. Pat. No. 7,653,438, which claims the benefit of U.S.Provisional Application Nos. 60/616,254, filed on Oct. 5, 2004; and60/624,793, filed on Nov. 2, 2004. Further, this application is acontinuation-in-part of U.S. patent application Ser. No. 10/408,665,filed on Apr. 8, 2003, now U.S. Pat. No. 7,162,303, which claims thebenefit of U.S. Provisional Patent Application Nos. 60/442,970, filed onJan. 29, 2003; 60/415,575, filed on Oct. 3, 2002; and 60/370,190, filedon Apr. 8, 2002.

(b) U.S. patent application Ser. No. 11/189,563, filed on Jul. 25, 2005,now U.S. Pat. No. 8,145,316.

(c) U.S. patent application Ser. No. 11/266,993, filed on Nov. 4, 2005,now U.S. Pat. No. 7,756,583.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and apparatus forneuromodulation. More particularly, the present invention relates tomethods and apparatus for achieving pulsed electric fieldneuromodulation via an intra-to-extravascular approach.

BACKGROUND

Congestive Heart Failure (“CHF”) is a condition that occurs when theheart becomes damaged and reduces blood flow to the organs of the body.If blood flow decreases sufficiently, kidney function becomes impaired,which results in fluid retention, abnormal hormone secretions andincreased constriction of blood vessels. These results increase theworkload of the heart and further decrease the capacity of the heart topump blood through the kidneys and circulatory system.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.Moreover, the fluid overload and associated clinical symptoms resultingfrom these physiologic changes result in additional hospital admissions,poor quality of life and additional costs to the health care system.

In addition to their role in the progression of CHF, the kidneys play asignificant role in the progression of Chronic Renal Failure (“CRF”),End-Stage Renal Disease (“ESRD”), hypertension (pathologically highblood pressure) and other cardio-renal diseases. The functions of thekidneys can be summarized under three broad categories: filtering bloodand excreting waste products generated by the body's metabolism;regulating salt, water, electrolyte and acid-base balance; and secretinghormones to maintain vital organ blood flow. Without properlyfunctioning kidneys, a patient will suffer water retention, reducedurine flow and an accumulation of waste toxins in the blood and body.These conditions result from reduced renal function or renal failure(kidney failure) and are believed to increase the workload of the heart.In a CHF patient, renal failure will cause the heart to furtherdeteriorate as fluids are retained and blood toxins accumulate due tothe poorly functioning kidneys.

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. An increase in renal sympathetic nerve activity leads tovasoconstriction of blood vessels supplying the kidneys, decreased renalblood flow, decreased removal of water and sodium from the body, andincreased renin secretion. Reduction of sympathetic renal nerveactivity, e.g., via denervation, may reverse these processes.

Applicants have previously described methods and apparatus for treatingrenal disorders by applying a pulsed electric field to neural fibersthat contribute to renal function. See, for example, co-pending U.S.patent application Ser. No. 11/129,765, filed on May 13, 2005, and Ser.No. 11/189,563, filed on Jul. 25, 2005, both of which are incorporatedherein by reference in their entireties. A pulsed electric field (“PEF”)may initiate renal neuromodulation, e.g., denervation, for example, viairreversible electroporation or via electrofusion. The PEF may bedelivered from apparatus positioned intravascularly, extravascularly,intra-to-extravascularly or a combination thereof. As used herein,electrofusion comprises fusion of neighboring cells induced by exposureto an electric field. Contact between target neighboring cells for thepurposes of electrofusion may be achieved in a variety of ways,including, for example, via dielectrophoresis. In tissue, the targetcells may already be in contact, thus facilitating electrofusion.

As used herein, electroporation and electropermeabilization are methodsof manipulating the cell membrane or intracellular apparatus. Forexample, the porosity of a cell membrane may be increased by inducing asufficient voltage across the cell membrane through, e.g., short,high-voltage pulses. The extent of porosity in the cell membrane (e.g.,size and number of pores) and the duration of effect (e.g., temporary orpermanent) are a function of multiple variables, such as field strength,pulse width, duty cycle, electric field orientation, cell type or sizeand other parameters.

Cell membrane pores will generally close spontaneously upon terminationof relatively lower strength electric fields or relatively shorter pulsewidths (herein defined as “reversible electroporation”). However, eachcell or cell type has a critical threshold above which pores do notclose such that pore formation is no longer reversible; this result isdefined as “irreversible electroporation,” “irreversible breakdown” or“irreversible damage.” At this point, the cell membrane ruptures and/orirreversible chemical imbalances caused by the high porosity occur. Suchhigh porosity can be the result of a single large hole and/or aplurality of smaller holes.

In some patients, when a PEF sufficient to initiate irreversibleelectroporation is applied to renal nerves and/or other neural fibersthat contribute to renal neural functions, applicants believe thatdenervation induced by the PEF would result in increased urine output,decreased plasma renin levels, decreased tissue (e.g., kidney) and/orurine catecholamines (e.g., norepinephrine), increased urinary sodiumexcretion, and/or controlled blood pressure that would prevent or treatCHF, hypertension, renal system diseases, and other renal orcardio-renal anomalies. PEF systems could be used to modulate efferentor afferent nerve signals, as well as combinations of efferent andafferent nerve signals.

A potential challenge of using intravascular PEF systems for treatingrenal disorders is to selectively electroporate target cells withoutaffecting other cells. For example, it may be desirable to irreversiblyelectroporate renal nerve cells that travel along or in proximity torenal vasculature, but it may not be desirable to damage the smoothmuscle cells of which the vasculature is composed. As a result, anoverly aggressive course of PEF therapy may persistently injure therenal vasculature, but an overly conservative course of PEF therapy maynot achieve the desired renal neuromodulation.

Applicants have previously described methods and apparatus formonitoring tissue impedance or conductivity to determine the effects ofpulsed electric field therapy, e.g., to determine an extent ofelectroporation and/or its degree of irreversibility. See, for example,Applicant's co-pending U.S. patent application Ser. No. 11/233,814,filed Sep. 23, 2005, which is incorporated herein by reference in itsentirety. Pulsed electric field electroporation of tissue causes adecrease in tissue impedance and an increase in tissue conductivity. Ifinduced electroporation is reversible, tissue impedance and conductivityshould approximate baseline levels upon cessation of the pulsed electricfield. However, if electroporation is irreversible, impedance andconductivity changes should persist after terminating the pulsedelectric field. Thus, monitoring the impedance or conductivity of targetand/or non-target tissue may be utilized to determine the onset ofelectroporation and to determine the type or extent of electroporation.Furthermore, monitoring data may be used in one or more manual orautomatic feedback loops to control the electroporation.

Regardless of whether or not monitoring techniques are utilized, theapplied energy or voltage from an intravascular PEF system necessary toestablish an electric field of sufficient magnitude in the vicinity oftarget neural fibers in order to modulate the target neural fibers maybe of a magnitude that causes persistent damage to non-target tissue,such as smooth muscle cells of the vessel wall. Thus, a desiredtreatment outcome, e.g., renal denervation, may not be achievable withsome intravascular PEF systems in certain patients without concomitantlyinducing persistent damage to the non-target tissue. It therefore wouldbe desirable to provide methods and apparatus for reducing the requiredmagnitude of applied energy or voltage necessary to achieve desiredneuromodulation in target tissue and/or to increase localization of thesufficient magnitude induced electric field to the vicinity of thetarget tissue.

SUMMARY

The present invention provides methods and apparatus for pulsed electricfield (“PEF”) neuromodulation via an intra-to-extravascular (“ITEV”)approach, e.g., to effectuate irreversible electroporation orelectrofusion, necrosis and/or inducement of apoptosis, alteration ofgene expression, changes in cytokine upregulation, and other conditionsin target neural fibers. In some embodiments, the ITEV PEF systemcomprises an intravascular catheter having one or more electrodesconfigured for intra-to-extravascular placement across a wall of apatient's vessel into proximity with target neural fibers. With theelectrode(s) passing from an intravascular position to an extravascularposition prior to delivery of the PEF, a magnitude of applied voltage orenergy delivered via the electrode(s) and necessary to achieve desiredneuromodulation may be reduced relative to an intravascular PEF systemhaving one or more electrodes positioned solely intravascularly. Themethods and apparatus of the present invention may, for example, be usedto modulate one or more target neural fibers that contribute to renalfunction.

Pulsed electric field parameters may be altered and combined in anycombination, as desired. Such parameters can include, but are notlimited to, voltage, field strength, pulse width, pulse duration, theshape of the pulse, the number of pulses and/or the interval betweenpulses (e.g., duty cycle), etc. For example, suitable field strengthscan be up to about 10,000 V/cm and suitable pulse widths can be up toabout 1 second. Suitable shapes of the pulse waveform include, forexample, AC waveforms, sinusoidal waves, cosine waves, combinations ofsine and cosine waves, DC waveforms, DC-shifted AC waveforms, RFwaveforms, square waves, trapezoidal waves, exponentially-decayingwaves, or combinations. The field includes at least one pulse, and inmany applications the field includes a plurality of pulses. Suitablepulse intervals include, for example, intervals less than about 10seconds. These parameters are provided as suitable examples and in noway should be considered limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the present invention will be apparent uponconsideration of the following detailed description, taken inconjunction with the accompanying drawings, in which like referencecharacters refer to like parts throughout, and in which:

FIG. 1 is a schematic view illustrating human renal anatomy.

FIG. 2 is a schematic detail view showing the location of the renalnerves relative to the renal artery.

FIGS. 3A and 3B are schematic side- and end-views, respectively,illustrating orienting of an electric field for selectively affectingrenal nerves.

FIGS. 4A-4D are schematic side-views, partially in section, illustratingmethods and apparatus for pulsed electric field neuromodulation via anintra-to-extravascular approach having a bipolar electrode pair with atleast one of the electrodes of the pair positioned extravascularly.

FIG. 5 is a schematic view, partially in section, illustrating methodsand apparatus for monopolar pulsed electric field neuromodulation via anintra-to-extravascular approach.

FIGS. 6A-6C are schematic side-views, partially in section, illustratingalternative embodiments of the methods and apparatus of FIG. 5, themethods and apparatus comprising a bipolar electrode pair having a firstelectrode positioned extravascularly and a second electrode positionedintravascularly.

FIGS. 7A and 7B are schematic side-views, partially in section,illustrating additional methods and apparatus for pulsed electric fieldneuromodulation via a bipolar electrode pair, the bipolar electrode paircomprising at least one first electrode positioned extravascularly andat least one second electrode positioned intravascularly.

FIGS. 8A-8C are a schematic side-sectional view and schematicside-views, partially in section, illustrating methods and apparatus forpulsed electric field neuromodulation having at least one bipolarelectrode pair with both electrodes of each electrode pair positionedextravascularly via an intra-to-extravascular approach.

FIG. 9 is a schematic side-view, partially in section, of an alternativeembodiment of the apparatus and methods of FIGS. 8.

FIGS. 10A-10F are schematic side-views, partially in section, ofalternative embodiments of the apparatus and methods of FIG. 9comprising multiple pairs of bipolar electrodes.

FIGS. 11A-11C are schematic side-views, partially in section, of analternative embodiment of the apparatus and methods of FIG. 10comprising a safety feature for intravascular delivery of the electrodesprior to extravascular placement.

FIG. 12 is a schematic side-view, partially in section, of methods andapparatus for pulsed electric field neuromodulation via at least oneangularly-aligned, longitudinally-spaced bipolar electrode pairpositioned extravascularly via an intra-to-extravascular approach.

FIGS. 13A-13D are schematic cross-sectional views along section line A-Aof FIG. 12, illustrating methods and apparatus for circumferentialpulsed electric field modulation of target neural fibers via multiplepairs of angularly-aligned, longitudinally-spaced ITEV bipolar electrodepairs, each pair positioned at a different circumferential position.

FIGS. 14A-14D are schematic side-sectional views and schematicside-views, partially in section, illustrating alternative methods andapparatus for pulsed electric field neuromodulation via electrodespositioned extravascularly via an intra-to-extravascular approach.

FIGS. 15A-15C are schematic side-views, partially in section, as well asa cross-sectional view along section line B-B of FIG. 15A, of furtheralternative methods and apparatus for pulsed electric fieldneuromodulation via electrodes positioned extravascularly via anintra-to-extravascular approach.

FIGS. 16A and 16B are schematic side-views of alternative embodiments ofthe methods and apparatus of FIGS. 15.

FIGS. 17A-17E are schematic side-views, partially in section, of stillfurther methods and apparatus for pulsed electric field neuromodulationvia electrodes positioned extravascularly via an intra-to-extravascularapproach.

FIGS. 18A-18D are schematic side-views, partially in section, ofalternative embodiments of the methods and apparatus of FIGS. 17.

FIGS. 19A and 19B are schematic side-views, partially in section, ofmethods and apparatus for pulsed electric field neuromodulationcomprising a stent having electrodes configured forintra-to-extravascular placement.

DETAILED DESCRIPTION A. Overview

The present invention relates to methods and apparatus forneuromodulation, e.g., denervation. More particularly, the presentinvention relates to methods and apparatus for achieving pulsed electricfield neuromodulation via an intravascular-to-extravascular approach. Insome embodiments, the ITEV PEF system comprises an intravascularcatheter having one or more electrodes configured forintra-to-extravascular placement across a wall of patient's vessel intoproximity with target neural fibers. With the electrode(s) passing froman intravascular position to an extravascular position prior to deliveryof the PEF, a magnitude of applied voltage or energy delivered via theelectrode(s) and necessary to achieve desired neuromodulation is reducedrelative to an intravascular PEF system having one or more electrodespositioned solely intravascularly. The methods and apparatus of thepresent invention may, for example, be used to modulate one or moretarget neural fibers that contribute to renal function.

The methods and apparatus of the present invention may be used tomodulate a neural fiber that contributes to renal function and mayexploit any suitable electrical signal or field parameters, e.g., anyelectric field that will achieve the desired neuromodulation (e.g.,electroporative effect). To better understand the structures of devicesof the present invention and the methods of using such devices for renalneuromodulation and monitoring, it is instructive to examine the renalanatomy in humans.

B. Selected Embodiments of Methods for Neuromodulation

With reference now to FIG. 1, the human renal anatomy includes kidneys Kthat are supplied with oxygenated blood by renal arteries RA, which areconnected to the heart by the abdominal aorta AA. Deoxygenated bloodflows from the kidneys to the heart via renal veins RV and the inferiorvena cava IVC. FIG. 2 illustrates a portion of the renal anatomy ingreater detail. More specifically, the renal anatomy also includes renalnerves RN extending longitudinally along the lengthwise dimension L ofrenal artery RA generally within the adventitia of the artery. The renalartery RA has smooth muscle cells SMC that surround the arterialcircumference and spiral around the angular axis θ of the artery. Thesmooth muscle cells of the renal artery accordingly have a lengthwise orlonger dimension extending transverse (i.e., non-parallel) to thelengthwise dimension of the renal artery. The misalignment of thelengthwise dimensions of the renal nerves and the smooth muscle cells isdefined as “cellular misalignment.”

Referring to FIG. 3, the cellular misalignment of the renal nerves andthe smooth muscle cells may be exploited to selectively affect renalnerve cells with reduced effect on smooth muscle cells. Morespecifically, because larger cells require a lower electric fieldstrength to exceed the cell membrane irreversibility threshold voltageor energy for irreversible electroporation, embodiments of electrodes ofthe present invention may be configured to align at least a portion ofan electric field generated by the electrodes with or near the longerdimensions of the cells to be affected. In specific embodiments, thedevice has electrodes configured to create an electrical field alignedwith or near the lengthwise dimension L of the renal artery RA to affectrenal nerves RN. By aligning an electric field so that the fieldpreferentially aligns with the lengthwise aspect of the cell rather thanthe diametric or radial aspect of the cell, lower field strengths may beused to affect target neural cells, e.g., to necrose or fuse the targetcells, to induce apoptosis, to alter gene expression, to change cytokineupregulation, and/or to induce other suitable processes. This isexpected to reduce total energy delivered to the system and to mitigateeffects on non-target cells in the electric field.

Similarly, the lengthwise or longer dimensions of tissues overlying orunderlying the target nerve are orthogonal or otherwise off-axis (e.g.,transverse) with respect to the longer dimensions of the nerve cells.Thus, in addition to aligning the PEF with the lengthwise or longerdimensions of the target cells, the PEF may propagate along the lateralor shorter dimensions of the non-target cells (i.e., such that the PEFpropagates at least partially out of alignment with non-target smoothmuscle cells SMC). Therefore, as seen in FIG. 3, applying a PEF withpropagation lines Li generally aligned with the longitudinal dimension Lof the renal artery RA is expected to preferentially causeelectroporation, electrofusion, denervation or other neuromodulation incells of the target renal nerves RN without unduly affecting thenon-target arterial smooth muscle cells SMC. The pulsed electric fieldmay propagate in a single plane along the longitudinal axis of the renalartery, or may propagate in the longitudinal direction along any angularsegment through a range of 0°-360°.

A PEF system placed within and/or at least partially across the wall ofthe renal artery, e.g., via an intra-to-extravascular (“ITEV”) approach,may propagate an electric field having a longitudinal portion that isaligned to run with the longitudinal dimension of the artery in theregion of the renal nerves RN and the smooth muscle cell SMC of thevessel wall so that the wall of the artery remains at leastsubstantially intact while the outer nerve cells are destroyed, fused orotherwise affected. Monitoring elements may be utilized to assess anextent of, e.g., electroporation, induced in renal nerves and/or insmooth muscle cells, as well as to adjust PEF parameters to achieve adesired effect.

C. Exemplary Embodiments of Systems and Additional Methods forNeuromodulation

With reference to FIG. 4, embodiments of intra-to-extravascular (“ITEV”)PEF systems and methods of the present invention are described. ITEV PEFsystems of the present invention are configured for temporaryintravascular placement and for passage of one or more electrodes acrossa wall of the vasculature for extravascular placement. Furthermore, thesystems are configured to deliver pulsed electric fields to neuralfibers for neuromodulation. In one particular example, the systems areconfigured to deliver the pulsed electric fields to neural fibers thatcontribute to renal function in order to achieve renal neuromodulation.For the purposes of the present invention, extravascular shall refer toany position external to the intima and media layers of the vasculature.Extravascular may, for example, include positions within the adventitiaof the vessel or within surrounding fatty tissue.

In FIGS. 4A-D, an ITEV PEF system 100 comprises an intravascularcatheter 102 having a lumen 103, a shaped cannula 104 configured forlow-profile delivery within the lumen 103 and for advancement from thelumen 103 in order to pierce the wall of a patient's vasculature, and afirst guide wire electrode 106 configured for advancement through alumen 105 of the cannula 104. The cannula 104 may, for example, befabricated from a shape memory material (e.g., Nitinol) or a flexible,pre-formed elastic material (e.g., thin-walled stainless steel).

In the embodiment of FIGS. 4A and 4B, system 100 further comprises asecond guide wire electrode 108 (FIG. 4B) configured for intravascularpositioning. The guide wire electrodes 106 and 108, which form a bipolarelectrode pair, optionally may be insulated at all regions, except theirdistal ends. The electrodes are electrically connected to a pulsedelectric field generator 50 (FIG. 4B) located external to the patient.The generator may be utilized with any embodiment of the presentinvention to deliver a PEF with desired field parameters. It should beunderstood that several examples of PEF-delivery electrodes describedbelow may be electrically connected to the generator even though thegenerator is not explicitly shown or described with each embodiment.

In use, the catheter 102 may be delivered to renal artery RA as shown inFIG. 4A, or it may be delivered through a guide catheter or other deviceto a renal vein or to any other vessel in proximity to target neuraltissue (e.g., target neural tissue that contributes to renal function).The catheter preferably is delivered via a percutaneous technique, suchas via a percutaneous femoral artery access. Once the shaped cannula 104is positioned within the patient's vasculature, it may be advanced pastthe outlet of the lumen 103 of the catheter 102 such that the cannula104 assumes a curved or otherwise angular profile. As the cannula 104advances further, it pierces the wall of the patient's vasculature to bepositioned extravascularly (i.e., at least within the adventitia). Thefirst guide wire electrode 106 is then advanced through the cannulalumen 105 such that a non-insulated distal region 109 a of the firstelectrode 106 is positioned extravascularly via anintra-to-extravascular approach. The cannula 104 may be retracted, andthe catheter 102, as well as the cannula 104 may be removed from thepatient or from the treatment site. The second guide wire electrode 108has a non-insulated distal region 109 b that is positionedintravascularly (before, during or after extravascular placement of thefirst electrode 106) to form a bipolar electrode pair with the firstelectrode 106 (FIG. 4B).

The first electrode 106 preferably comprises the active electrode andthe second electrode 108 preferably comprises the return electrode.However, it should be understood that the electrode polaritiesoptionally may be reversed. The non-insulated distal regions 109 a-b ofthe electrodes 106 and 108 optionally may be in substantial alignmentalong a cross-sectional plane through renal artery RA. Alternatively,the distal regions 109 a-b may be spaced apart longitudinally. Suchlongitudinal spacing of the distal regions 109 a-b may, for example,better align a pulsed electric field delivered across the electrodeswith a longitudinal dimension of the renal artery to facilitatemodulation of renal nerves with limited effect on non-target smoothmuscle cells or other cells, as described previously with respect toFIG. 3.

With the first and second electrodes 106 and 108 positioned as desired,a pulsed electric field generated by the PEF generator 50 is transmittedthrough the electrodes 106 and 108 and delivered across thenon-insulated distal regions 109 a-b of the electrodes. The PEF therapymodulates activity along neural fibers that directly or indirectlycontribute to renal function (e.g., denervates neural fibers related torenal function). This may be achieved, for example, via irreversibleelectroporation, electrofusion, necrosis and/or inducement of apoptosisin the nerve cells, alteration of gene expression, changes in cytokineupregulation, and/or other suitable processes. After delivery of PEFtherapy, the ITEV PEF system 100 may be removed from the patient toconclude the procedure.

It is expected that PEF therapy using the ITEV PEF system 100 willalleviate clinical symptoms of CHF, hypertension, renal disease and/orother cardio-renal diseases for a period of months, potentially up tosix months or more. This time period might be sufficient to allow thebody to heal; for example, this period might reduce the risk of CHFonset after an acute myocardial infarction, thereby alleviating a needfor subsequent re-treatment. Alternatively, as symptoms reoccur, or atregularly scheduled intervals, the patient might return to the physicianfor a repeat therapy.

In order to denervate or otherwise modulate target neural fibers, theITEV PEF system 100 should generate an electric field of sufficientstrength or magnitude across the fibers to induce such denervation ormodulation. When utilizing an intravascular PEF system, depending uponthe arrangement and positioning of the PEF electrodes, as well as thephysiology of the patient, the applied voltage necessary to achieve afield strength of sufficient magnitude at the target neural fibers alsomay be of sufficient magnitude to induce undesirable persistent injuryin non-target tissue, such as smooth muscle cells and/or the vesselwall. It is expected that the extravascular positioning of electrode 106via an intra-to-extravascular approach will reduce the necessary appliedvoltage for denervation or modulation (e.g., renal denervation ormodulation) via PEF therapy compared to the applied voltage requiredwhen utilizing solely intravascular apparatus with similarly spaced andsized electrodes. Specifically, extravascular placement of electrode 106in closer proximity to the target neural fibers is expected to increaselocalization of the peak induced electric field to the vicinity of thetarget neural fibers.

As seen in FIG. 4C, the catheter 102 optionally may comprise anexpandable element 101 (e.g., an inflatable balloon) that stabilizes thecatheter 102 within the patient's vessel. The expandable element 101further facilitates piercing of the vessel wall with the cannula 104 toposition the first electrode 106 at an extravascular location. As seenin FIG. 4D, the first electrode 106 may comprise a spaced bipolarelectrode pair 107 a and 107 b to obviate the need for the intravascularsecond electrode 108. The PEF therapy may be delivered extravascularlyacross the bipolar electrode pair 107 a-b.

The extravascular second electrode 106 optionally may be replaced with avirtual electrode. For example, conductive saline may be injectedthrough cannula 104 into the extravascular space. The conductive salinemay provide a virtual electrode surrounding all or part of thecircumference of the vessel and may be used in a bipolar fashion withintravascular electrode 108.

The examples of the ITEV PEF systems of FIGS. 4A-D optionally may beutilized in a monopolar fashion by replacing the intravascular secondelectrode 108 with a ground pad coupled to the PEF generator 50 andattached to the exterior of the patient. FIG. 5 illustrates analternative monopolar ITEV PEF system 110 comprising a catheter 112having an expandable element 114 with one or more needle-like ITEVelectrodes 116 coupled to the expandable element. When multiple needleelectrodes 116 are provided, they may be spaced circumferentially and/orlongitudinally about/along the expandable element 114. The system 110further comprises a ground pad 120 attached to the skin S of the patientalong the exterior of the patient (e.g., to the patient's flank, back orthigh) and coupled to the PEF generator 50 as a return electrode. Theground pad 120 optionally may be positioned directly lateral to the ITEVelectrode(s) 116 to direct the PEF therapy along the patient'svasculature (e.g., along renal artery RA).

The expandable element 114 comprises a member or structure configuredfor intravascular delivery to (and retrieval from) a target location ina low profile configuration and for expansion to an expanded deployedconfiguration at the target location. The expandable element 114 maycomprise, for example, an inflatable balloon, an expandable basket orcage, or other expandable structure. As seen in FIG. 5, expansion of theexpansion element 114 causes the ITEV electrode(s) 116 to pierce thewall of renal artery RA and move from an intravascular location to anextravascular location. With the ITEV electrode(s) 116 positionedextravascularly and coupled to the PEF generator 50, the ITEVelectrode(s) may be energized as active electrodes in a monopolar PEFtherapy with the external ground pad 120 serving as the returnelectrode.

Referring now to FIGS. 6A-C, alternative embodiments of the ITEV PEFsystem 110 are described comprising a first electrode positionedextravascularly and a second electrode positioned intravascularly. InFIGS. 6A-C, the ITEV PEF systems 110 again comprise the catheter 112having the expandable element 114 with one or more ITEV electrodes 116coupled to the expandable element and configured forintra-to-extravascular delivery. The systems 110 further comprise anintravascular second electrode 118 positioned within the vessel. In FIG.6A, the second electrode 118 comprises a guidewire electrode positionedwithin the lumen of the catheter 112. The guidewire electrode 118 iscoupled to the PEF generator 50 and is insulated at regions other than adistal region positioned distal of the catheter 112. In FIG. 6B, thesecond electrode 118 is coupled to the shaft of the catheter 112distally of the expandable element 114. In FIG. 6C, the second electrode118 is coupled to the shaft of catheter 112 proximally of the expandableelement 114. In use, the ITEV electrode(s) 116 may comprise activeelectrode(s) and the second electrode 118 may comprise a returnelectrode, or vice versa. The second electrode 118 optionally may belongitudinally spaced relative to the ITEV electrode(s) 116 to align thePEF therapy with a longitudinal axis of the patient's vasculature, asdescribed previously with respect to FIGS. 2 and 3. The secondelectrodes 118 may, for example, be fabricated from wound coils of wire.When utilizing relatively long electrodes, wound coils allow thecatheter 112 to maintain desired flexibility.

Referring now to FIGS. 7A and 7B, additional methods and apparatus forpulsed electric field neuromodulation via a bipolar electrode pairhaving a first electrode positioned extravascularly and a secondelectrode positioned intravascularly are described. FIGS. 7A and 7B,more specifically, illustrate an ITEV PEF system 150 comprising acatheter 152 and an expandable element 154, which may comprise aninflatable balloon or an expandable wire cage. The system 150 furthercomprises one or more ITEV needle electrodes 156 that are coupled to thecatheter 152, illustratively proximal of expandable element 154, andreturn electrode 157, illustratively coupled to the shaft of catheter152 distal of expandable element 154. Additionally, the system comprisesa protective sheath 158 having a lumen 159 in which the catheter 152 maybe positioned for percutaneous advancement and/or retrieval.

In FIGS. 7A and 7B, the distal regions of the ITEV electrodes 156 extendlaterally over, but are not connected to, at least a portion of theexpandable element 154. This is in contrast to the previously describedITEV PEF systems of FIGS. 4-6 that have ITEV electrodes coupled directlyto an expandable element. By separating the ITEV electrode(s) 156 fromthe expandable element 154, the system 150 of FIGS. 7A and 7B maysimplify manufacturing and/or enhance expansion reliability.

As seen in FIG. 7A, the catheter 152 and the protective sheath 158 maybe advanced into position within the patient's vasculature (e.g., withinrenal artery RA over guidewire G). Once in position, the sheath 158 maybe retracted relative to the catheter 152 and/or the catheter 152 may beadvanced relative to the sheath 158 such that the expandable element154, the ITEV electrode(s) 156 and the return electrode 157 arepositioned distally of the protective sheath 158. As seen in FIG. 7B,the expandable element 154 then may be expanded, such that the ITEVneedle electrode(s) 156 puncture the vessel wall and are positionedextravascularly via an ITEV approach. Once the electrode(s) 156 arepositioned extravascularly, PEF therapy may proceed between the ITEVelectrode(s) 156 and the return electrode 157. The PEF therapy, forexample, can modulate and/or denervate a neural fiber that contributesto renal function. Upon completion of the PEF therapy, the expandableelement 154 may be collapsed, and the sheath 158 may be advancedrelative to the catheter 152, such that the ITEV electrodes 156 areremoved from the vessel wall. The system 150 then may be removed fromthe patient to complete the procedure.

Referring now to FIGS. 8A-C, methods and apparatus for pulsed electricfield neuromodulation are described utilizing one or more bipolarelectrode pairs with both electrodes of each pair positionedextravascularly via an intra-to-extravascular approach. One example ofsuch an ITEV PEF system 170 comprises a catheter or sheath 172 havingshaped ITEV bipolar needle electrodes 174 a and 174 b that areconfigured for advancement to an intravascular location within thesheath. The electrodes 174 a-b may have shape-memory properties (e.g.,may be fabricated from a shape-memory alloy such as Nitinol) and may beinsulated at locations other than their distal regions. As seen in FIG.8B, upon advancement of the electrodes 174 a-b to a position distal ofthe sheath 172 (e.g., via retraction of the sheath), the electrodes 174a-b assume their preformed shape and puncture the wall of the patient'svasculature, illustratively renal artery RA, such that the distalregions of the electrodes 174 a-b are positioned extravascularly via anITEV approach. As will be apparent, electrodes 174 a and 174 b may belongitudinally spaced relative to one another to better align the PEFtherapy with a longitudinal dimension of the patient's vasculature.Furthermore, although the electrodes illustratively are spaced radiallyabout 180° apart, it should be understood that the electrodesalternatively may be spaced with any desired radial separation (or lackthereof).

FIG. 8C illustrates another example of the ITEV PEF system 170comprising multiple pairs of ITEV electrodes that are longitudinallyspaced. The system 170, for example, can comprise a first bipolarelectrode pair 174 a and 174 b, and a second bipolar electrode pair 174a′ and 174 b′. Additional pairs of bipolar electrodes at differentcircumferential positions or with different longitudinal spacing may beutilized as desired in other examples.

Once properly positioned, PEF therapy may be delivered across theelectrodes 174 to achieve desired neuromodulation. Upon completion ofthe PEF therapy, the needle electrodes 174 may be retracted relative tothe sheath 172, and/or the sheath 172 may be advanced relative to theelectrodes 174, such that the electrodes are removed from the wall ofthe patient's vasculature and coaxed back into a constrained retrievalconfiguration within the sheath. The ITEV PEF system 170 then may beremoved from the patient to complete the procedure.

With reference to FIG. 9, an alternative embodiment of the ITEV PEFsystem 170 is described comprising a catheter 176 having an expandableelement 177. The expandable element 177 acts as a guide that, whenexpanded, directs or forces the electrodes 174 across the vessel wall.More specifically, the expandable element 177 can direct the electrodes174 through the vessel wall by advancing the electrodes 174 along theexpandable element 177 after it has been expanded. Alternatively, theexpandable element 177 can force the electrodes 174 across the vesselwall by advancing the electrodes 174 over the expandable element 177while the expandable element 177 is in a reduced profile configurationand then expanding of the expandable element 177 to force the electrodes174 across the wall of the vessel.

FIGS. 10A-F illustrate additional alternative embodiments of the ITEVPEF system 170 comprising multiple pairs of bipolar electrodes. In FIGS.10A and 10B, the ITEV electrodes 174 have been replaced with ITEVelectrode carriers 178. Each ITEV electrode carrier 178 comprisesmultiple electrodes 179. For example, each electrode carrier 178 maycomprise a pair of electrically-isolated bipolar electrodes 179.Alternatively, each carrier 178 may comprise multiple electrodes 179 ofa common polarity. The electrodes 179 comprise sharpened points, pins,or other raised features for penetrating the wall of the patient'svasculature. As seen in FIG. 10A, the electrodes 179 may be delivered tothe stimulation site in a low profile configuration, e.g., through orwithin the sheath 172. The electrodes 179 then may be positionedextravascularly via an ITEV approach by expanding the expandable element177, as in FIG. 10B.

As seen in FIGS. 10C and 10D, the electrode carriers 178 optionally maybe coupled to a catheter 176 distal of the expandable element 177 at acollar 175. The collar 175 may be slidingly attached to the catheter 176and/or may be longitudinally constrained. An expected benefit ofattaching the carriers to the catheter is good control of theextravascular positioning of electrodes 179 via an ITEV approach.

As seen in FIG. 10E, the electrode carriers 178 optionally may spiralaround the expandable element 177. The carriers 178 optionally maycomprise several electrodes 179 positioned at multiple circumferentialpositions to facilitate more circumferential PEF therapy. The electrodecarriers 178 preferably are electrically isolated from one another. Forexample, the carriers 178 may be insulated at all regions except for atthe electrodes 179.

As seen in FIG. 10F, the system 170 optionally may comprise a singleelectrode carrier 178 that spirals around the expandable element 177. Aplurality of the electrodes along the unitary carrier may be of a commonpolarity and/or may be electrically isolated from one another and ofvarying polarity to form bipolar electrode pair(s). The electrodes 179may be positioned a multiple circumferential positions, as desired.

FIGS. 11A-C show additional examples of the ITEV PEF system 170comprising a safety feature that facilitates intravascular delivery ofthe electrodes 179 prior to extravascular placement of the electrodes.In the embodiment of FIGS. 11A-C, the electrodes 179 are coupled toelectrode carriers 178 in a manner that facilitates rotation of theelectrodes 179 relative to the respective carriers 178. For example, theelectrodes 179 may be coupled to the carriers 178 at pivots 180, whichmay comprise rotational bearing surfaces. Furthermore, the electrodes179 comprise extensions 182 that co-act with the expandable element 177to selectively rotate the electrodes 179 between a reduced delivery andretrieval profile and an expanded profile suitable for ITEV delivery ofthe electrodes. The electrodes 179 optionally may be biased towards thereduced profile, e.g., via a spring mechanism. The reduced profileserves as a safety feature that reduces a risk of inadvertentperforation of vascular tissue prior to ITEV placement of the electrodesat a treatment site.

As seen in FIG. 11A, the electrodes 179 lie flat near or against theelectrode carrier 178 during delivery to an intravascular treatment site(e.g., through or within the sheath 172). The electrodes 179 arepositioned proximal of the expandable element 177 during delivery. Oncepositioned within the vessel, the electrodes 179 are expanded such thattheir tips point radially outward by retracting the expandable element177 relative to the electrode carriers 178. As seen in FIG. 11B,retraction of the expandable element 177 causes it to engage theextensions 182 of the electrodes 179 such that the electrodes 179 rotateabout the pivots 180 to the expanded configuration suitable for ITEVdelivery of the electrodes 179. The expandable element 177 then isexpanded, such that the electrodes 179 are forced through the vesselwall via an ITEV approach, as in FIG. 11C. ITEV PEF therapy then mayproceed, as desired. Upon completion of the therapy, the expandableelement 177 and the electrodes 179 are returned to the reduced profileconfiguration for retrieval from the patient.

With reference now to FIG. 12, methods and apparatus for pulsed electricfield neuromodulation via at least one angularly-aligned,longitudinally-spaced bipolar electrode pair positioned extravascularlyvia an intra-to-extravascular approach are described. FIG. 12, morespecifically, shows an example of an ITEV PEF system 200 that comprisesa catheter 202 having an expandable element 204 with at least one pairof longitudinally-spaced bipolar needle electrodes 206 a and 206 b. Theneedle electrodes 206 a-b are positioned at substantially the sameangular position along the expandable element (in FIG. 12, the systemillustratively comprises two pairs of longitudinally-spaced,angularly-aligned bipolar electrodes 206 a-b positioned at distinctcircumferential positions). Angular alignment of thelongitudinally-spaced bipolar electrodes 206 a-b may align the PEFtherapy with a longitudinal axis of target neural fibers, as describedpreviously. The bipolar pairs of needle electrode 206 may comprise anydesired longitudinal spacing; for example, the electrodes may comprisespacing in the range of about 0.5-10 mm.

The ITEV PEF system 200 may be delivered to an intravascular treatmentsite, such as a site within renal artery RA, using well-knownpercutaneous techniques. For example, the system 200 may be advancedover a guidewire G positioned with a lumen 203 of a catheter 202, whichmay be advanced through/within a guide catheter or a sheath 210. Oncepositioned at the treatment site, an expansion element 204 is expandedto force the bipolar needle electrodes 206 across the wall of the vesselsuch that the ends of the electrodes 206 are positioned extravascularlyvia an ITEV approach. The expansion element 204 may, for example, beexpanded by (a) inflating a balloon, (b) self-expanding a basket or cageafter positioning the element 204 distal of sheath 210, and/or (c)mechanical expanding a basket or cage via various push/pull and/ortension/compression techniques.

Positioning the electrodes 206 using an ITEV technique places theelectrodes in closer proximity to target neural fibers that contributeto renal function. As discussed previously, renal nerves may be locatedin the adventitia of the renal arteries and/or in tissue immediatelysurrounding the renal arteries. Such ITEV positioning of the electrodes,as well as selected angular alignment of the bipolar electrode pair(s),may reduce energy requirements necessary to achieve desiredneuromodulation, as compared to a PEF system comprisingintravascularly-positioned electrodes.

The electrodes 206 preferably are of small enough caliber to safelycross the wall of renal artery RA without significant risk of bleeding,vessel wall injury, etc. For example, the electrodes may be of a caliberless than about 23 Gauge. Furthermore, the electrodes may be solid ormay comprise one or more lumens. When with lumen(s), the needleelectrodes may be configured for infusion of agents that either enhancethe desired neuromodulatory effect (e.g., saline injection may be usedto locally enhance conductivity during PEF therapy) or provideprotective effects (e.g., cooling agents may be injected to protectnon-target tissues).

The needle electrodes 206 also may be conductive along their entirelengths or may be insulated along at least part of their lengths. Forexample, the needle electrodes 206 can be insulated at locations otherthan their distal ends. Insulation along part of the lengths ofelectrodes 206 may reduce undesirable delivery of pulsed electric fieldtherapy to non-target tissues, e.g., the intima or to the media of thepatient's vessel. Such insulated electrodes preferably comprise lengthssufficient to place the non-insulated portions of the electrodesextravascularly at positions at least within the vasculature adventitiaduring ITEV positioning of the electrodes.

Referring now to FIGS. 13A-D, methods and apparatus for circumferentialpulsed electric field modulation of target neural fibers via multiplepairs of angularly-aligned, longitudinally-spaced ITEV bipolar electrodepairs in which each electrode pair is positioned at a differentcircumferential position. FIGS. 13A-D illustrate several examples of theITEV PEF system 200 along section line A-A of FIG. 12. In FIG. 13A, theITEV PEF system 200 comprises two pairs of angularly-aligned,longitudinally-spaced bipolar electrodes 206 circumferentiallypositioned approximately 180° apart, as in FIG. 12. In FIG. 13B, thesystem 200 comprises three pairs of such bipolar electrodes spacedapproximately 120° apart. In FIG. 13C, the system 200 comprises fourpairs spaced roughly 90° apart, and in FIG. 13D, the system 200comprises eight pairs spaced about 45° apart. As will be apparent, anydesired number of electrode pairs may be provided. Furthermore, althoughthe electrode pairs shown in FIGS. 13A-D have been equallycircumferentially spaced, they alternatively may be circumferentiallyspaced at any other desired spacing, including any other desired unequalcircumferential spacing.

As illustrated by field lines L in FIGS. 13A-D, the tissue regionaffected by PEF therapy delivery across each bipolar electrode pair,e.g., the tissue region experiencing desired neuromodulation, isconfined to a narrow circumferential segment of the treatment site.Providing multiple pairs of bipolar ITEV electrode pairs 206 may providea more circumferential treatment. As seen in FIG. 13D, adding additionalpairs of ITEV bipolar electrodes 206 eventually causes thecircumferentially-affected segments to overlap, thereby providing fullcircumferential treatment. In some cases, it may be desirable to providefull circumferential treatment, while in other cases it may be desirableto provide less than complete circumferential treatment. The medicalpractitioner may provide any desired level of circumferential treatmentand/or may utilize any desired number of circumferentially-spacedbipolar electrode pairs. Circumferential PEF therapy along alongitudinal segment of the patient's vessel may be achieved bycollapsing the expansion element 204, rotating the catheter 202 adesired amount about its longitudinal axis, and then re-expanding theexpansion element 204 to re-position electrode pairs 206 extravascularlyfor treatment of another circumferential longitudinal segment of thepatient's vessel. This process can be repeated at a single longitudinallocation as desired.

FIGS. 14A and 14B show additional ITEV PEF systems 300 that comprise acatheter 302 having an outer sheath 304, a guidewire tube 306, and anatraumatic nosecone 308. The guidewire tube 302 is coupled to andextends through or communicates with a lumen 309 of the atraumaticnosecone 308. The system 300 also includes a number ofproximally-oriented ITEV needle electrodes 310 coupled to the nosecone308 at their distal regions, and a pusher tube 312 coaxially positionedabout the guidewire tube 306. The pusher tube 312 optionally has aflared tip 314, which may be relatively stiff and/or radiopaque. Theelectrodes 310 may be coupled to the PEF generator 50 via electricalcontacts formed with or within the guidewire tube 306 (e.g., via ametallic braid, coil or wire on or near an outer diameter of theguidewire tube). The electrodes 310 may physically contact theseelectrical contacts to facilitate delivery of PEF therapy. In someembodiments, the flared tip 314 completes the circuit upon contactingthe electrodes, as in FIG. 14B.

FIG. 14A shows the system 300 in the reduced delivery and retrievalconfiguration with the electrodes 310 positioned within the sheath 304.Upon intravascular placement at a treatment site, the sheath 304 isretracted and/or the guidewire tube 306 is advanced, such that theelectrodes 310 are removed from the sheath 304. The electrodes 310preferably are fabricated from an elastic material that resistsdeformation and applies a restoring force upon deformation. Furthermore,the electrodes 310 preferably are coupled to the nosecone 308 in amanner that biases the electrodes 310 to the reduced profile shown inFIG. 14A.

As seen in FIG. 14B, when the catheter 302 is positioned at a treatmentsite (e.g., within the renal artery RA), the pusher tube 312 is advancedrelative to the guidewire tube 306 such that the flared tip 314 engagesand elastically deforms the electrodes 310 radially outward. Theelectrodes 310 pierce the vessel to position the tips of the electrodesextravascularly via an ITEV approach. The catheter 302 optionally may beretracted after deformation of the electrodes 310 to engage theelectrodes with the patient's vessel and place the electrodesextravascularly. PEF therapy then may proceed to achieve desiredneuromodulation. Upon completion of the treatment, the pusher tube 312is retracted relative to the guidewire tube 306 and the electrodes 310.The guidewire tube 306 is advanced slightly to release the electrodes310 from the vessel wall. The restoring force provided by the electrodes310 returns the electrodes 310 to the reduced at-rest profile. Thesheath 304 then may be advanced relative to the guidewire tube 306, suchthat the needle electrodes 310 are once again positioned within thesheath 304 as in FIG. 16A for retrieval and removal from the patient.

In an additional or alternative embodiment of the apparatus of FIGS. 14Aand 14B, the needle electrodes 310 may be replaced with needle housingsthrough which the needle electrodes may be advanced. The needle housingsare expanded into contact with a vessel wall, and the needle electrodesthen are advanced across the vessel wall. Such advancement may beaccomplished via a variety of mechanical means. For example, advancementof the pusher tube past a specified position relative to the guidewiretube, the nosecone and/or the needle housings may release aspring-loaded member that advances the needles.

FIGS. 14C and 14D illustrate an alternative embodiment of the ITEV PEFsystem 300 comprising one or more longitudinally spaced pairs of bipolarelectrodes. In FIGS. 14C and 14D, needle electrodes 310 a are coupled tothe nosecone 308, and needle electrodes 310 b are coupled to a proximalregion of a first flared tip 314 a of a first pusher tube 312 a. Thesystem 300 further comprises a second pusher tube 312 b having a secondflared tip 314 b. The second pusher tube 312 b is coaxially disposedabout the first pusher tube 312 a.

Electrodes 310 a and 310 b form one or more longitudinally spaced pairsof bipolar electrodes. For example, electrodes 310 a may comprise activeelectrodes and electrodes 310 b comprise return electrodes, or viceversa. As seen in FIG. 14C, the electrodes may be delivered within thesheath 304. Once positioned at a treatment site, the sheath 304 may bewithdrawn, and the electrodes 310 may be positioned extravascularly viaan ITEV approach, as in FIG. 14D. Specifically, the first pusher tube312 a may be advanced relative to the guidewire tube 306, such thatfirst flared tip 314 a impinges upon and deforms the needle electrodes310 a. This urges the electrodes 310 a across the vessel wall. Likewise,the second pusher tube 312 b may be advanced relative to the firstpusher tube 312 a such that the second flared tip 314 b impinges uponand deforms the needle electrodes 310 b. This mechanism urges theelectrodes 310 b across the vessel wall. In the embodiment of FIGS. 14Cand 14D, the flared tips 314 comprise distal profiles that providegradual transitions for deforming the electrodes 310.

FIGS. 15A-C show examples of another ITEV PEF system 320 that comprisesa catheter 322 having (a) a plurality of proximal electrode lumens 324terminating at proximal side ports 325, (b) a plurality of distalelectrode lumens 326 terminating at distal side ports 327, and (c) aguidewire lumen 323. The catheter 322 preferably comprises an equalnumber of proximal and distal electrode lumens. The system 320 alsoincludes proximal needle electrodes 328 that may be advanced through theproximal electrode lumens 324 and needle electrodes 329 that may beadvanced through the distal electrode lumens 326.

As illustrated in FIG. 15A, the catheter 322 may be advanced over theguidewire 321 via the lumen 323 to a treatment site within the patient'svasculature (e.g., to a treatment site within the patient's renal arteryRA). During intravascular delivery, the electrodes 328 and 329 arepositioned such that their non-insulated and sharpened distal regionsare positioned within the lumens 324 and 326, respectively. Oncepositioned at a treatment site, a medical practitioner may advance theelectrodes via their proximal regions that are located external to thepatient. As seen in FIG. 15B, such advancement causes the distal regionsof the electrodes 326 and 329 to exit side ports 325 and 327,respectively, and pierce the wall of the patient's vasculature such thatthe electrodes are positioned extravascularly via an ITEV approach.

The proximal electrodes 328 can be connected to PEF generator 50 asactive electrodes and the distal electrodes 329 can serve as returnelectrodes. In this manner, the proximal and distal electrodes formbipolar electrode pairs that align PEF therapy with a longitudinal axisor direction of the patient's vasculature. As will be apparent, thedistal electrodes 329 alternatively may comprise the active electrodesand the proximal electrodes 328 may comprise the return electrodes.Furthermore, the proximal and/or the distal electrodes may comprise bothactive and return electrodes. Any combination of active and distalelectrodes may be utilized, as desired.

When the electrodes 328 and 329 are positioned extravascularly, PEFtherapy may proceed to achieve desired neuromodulation. After completionof the PEF therapy, the electrodes may be retracted within lumens 324and 326. The catheter 322, as well as the guidewire 321 then may beremoved from the patient to complete the procedure. Additionally oralternatively, the catheter may be repositioned to provide PEF therapyat another treatment site.

FIGS. 16A and 16B show alternative embodiments of the ITEV PEF system320. In FIG. 16A, the catheter 322 of the system 320 further comprisesan expandable centering element 330, which may comprise an inflatableballoon or an expandable basket or cage. In use, a centering element 330may be expanded prior to deployment of the needle electrodes 328 and 329to center the catheter 322 within the patient's vessel (e.g., withinrenal artery RA). Centering the catheter 322 is expected to facilitatedelivery of all needle electrodes to desired depths within/external tothe patient's vessel (e.g., to deliver all of the needle electrodes tothe same depth).

In FIG. 16A, the illustrated centering element 330 is positioned betweenthe proximal side ports 325 and the distal side ports 327, i.e., betweenthe delivery positions of the proximal and distal electrodes. However,it should be understood that centering element 330 additionally oralternatively may be positioned at a different location or at multiplelocations along the length of catheter 322 (e.g., at a location proximalof side ports 325 and/or at a location distal of side ports 327). InFIG. 16B, the system 320 illustratively comprises a first centeringelement 330 a positioned proximal of the proximal side ports 325 and asecond centering element 330 b positioned distal of the distal sideports 327.

Referring now to FIGS. 17A-E, ITEV PEF systems 350 utilizing one or morehypotubes are described. In the embodiment of FIGS. 17A and 17B, theITEV PEF system 350 comprises a catheter 352 having an outer sheath 354,an outer shaft 356, a hypotube 358 with multiple distal extensions 359,and an inner shaft 360 with a guide block 362. The inner shaft 360terminates at an atraumatic tip 364, and a guidewire lumen preferablyextends through the inner shaft and the atraumatic tip. The hypotube 358is connected proximally to the outer shaft 356, and the outer shaft 356is coaxially positioned over the inner shaft 360.

The hypotube 358 can have extensions 359 that may be fabricated bycutting away portions of the hypotube. The hypotube 358 may befabricated from a conductive material, such as a metal alloy orplatinum, or the hypotube may comprise a relative non-conductivematerial. The extensions 359 may be selectively insulated and/ornon-insulated, and they may be electrically coupled to the PEF generator50 to provide one or more extension electrodes. The extension electrodesmay, for example, be etched onto the hypotube and its extensions, e.g.,via a metal deposition process. Electrical contacts for energy deliverymay be exposed at the tips of insulated extensions 359; alternatively,the non-insulated contacts may extend across all or part of the lengthsof the extensions. Furthermore, the entire hypotube 358 may comprise anelectrode when the hypotube is fabricated from a conductive material.

The extension electrode(s) 359 may be of a common polarity or may be ofdifferent polarities. When of different polarities, PEF therapy may bedelivered across the electrodes in a bipolar fashion. When of commonpolarity, the electrodes may be utilized in a monopolar fashion, e.g.,with an external ground pad. Alternatively, the catheter 352 optionallymay comprise one or more additional electrodes of opposite polarityalong its length that may be utilized in a bipolar fashion with theextension electrode(s) 359 of the hypotube 358. In one embodiment, theouter shaft 356 comprises at least a second hypotube along its lengthhaving extension electrode(s) that serve as the additional electrode(s)of opposite polarity and may be utilized to form spaced bipolarelectrode pair(s) for delivery of the PEF therapy.

As seen in FIG. 17A, the catheter 352 may be advanced to a treatmentsite within a patient's vasculature, such as a treatment site withinrenal artery RA, using well-known percutaneous techniques (e.g., througha guide catheter). Once properly positioned, the outer sheath 354 may beretracted to expose the hypotube 358, and then the outer shaft 356 maybe advanced relative to inner shaft 360 to drive the extensions 359against the guide block 362. As seen in FIG. 17B, the guide block 362provides a tapered transition that progressively deforms extensions 359in an elastic or plastic manner as the outer shaft 354 is advancedrelative to the inner shaft 360. This deformation directs the extensions359 radially outward to detone the extension electrodes. Continuedadvancement of the outer shaft causes the extension electrodes topenetrate the vessel wall and to be positioned extravascularly via anITEV approach. With the extension electrodes 359 positionedextravascularly, PEF therapy may proceed.

Upon completion of the PEF therapy, the extensions 359 once again may becollapsed against the outer shaft 356 for retrieval of the system 350from the patient. If the deformation of the extensions 359 compriseselastic deformation, the outer shaft 356 may be retracted relative tothe wall of renal artery RA to remove the extensions from the wall. Theextensions 359 then will return to their at-rest configuration of FIG.17A. If the deformation is plastic, then the extensions 359 may, forexample, be collapsed by advancing the outer sheath 354 or a guidecatheter over the outer shaft 356 such that the sheath 354 abuts thebases of the extensions 359. The outer shaft 356 then may be retractedwhile the sheath 354 is held stationary or advanced relative to theouter shaft to collapse the extensions 359 within the sheath 354 forretrieval of the system 350 from the patient.

As seen in FIGS. 17C and 17D, the ITEV PEF system 350 optionally maycomprise one or more longitudinally spaced pairs of ITEV electrodes. InFIGS. 17C and 17D, the hypotube 358 comprises distal extensions 359 aand proximal extensions 359 b. The distal extensions 359 a may bedeployed extravascularly in the manner described previously. For ITEVdeployment of the proximal extensions 359 a, the system 350 furthercomprises a proximal pusher tube 355 having a distally-oriented guideblock 362′ for deforming the proximal extensions 359 b. The pusher tube355 is coaxially disposed over the outer shaft 356, but within the outersheath 354. As seen in FIG. 17D, the pusher tube 355 may be advancedrelative to the outer shaft 356 in order to deform the proximalextensions 359 b and position the extension electrodes extravascularlyvia an ITEV approach. The proximal and distal extension electrodes ofthe hypotube 358 form one or more longitudinally spaced bipolarelectrode pairs.

In FIG. 17E, ITEV PEF system 350 again comprises the distal extensions359 a and the proximal extensions 359 b. However, in the embodiment ofFIG. 17E, the proximal and distal extensions are all distally-oriented,with the distal extensions 359 a being of a greater length than theproximal extensions 359 b. During extravascular placement of theextensions, the additional length of the distal extensions 359 a causesthe distal extensions to pierce the wall of the patient's vessel moredistally than do the proximal extensions 359 b. In this manner, theproximal and distal extensions 359 a-b are longitudinally spaced apartfrom one another when deployed extravascularly. After completion ofextravascular PEF therapy, the distal orientation of the proximal anddistal extensions 359 a-b facilitates collapse and retrieval of theextensions. The outer shaft 356 may be retracted while the sheath 354 isheld stationary or advanced relative to the outer shaft to collapse theextensions 359 a-b within the sheath 354 for retrieval of the system 350from the patient.

Although several examples of the ITEV systems 350 shown in FIGS. 17A-Eillustrate deployment of the ITEV extension electrodes 359 via guideblock(s) 362, it should be understood that the electrodes may bedeployed via a variety of alternative techniques. For example, apush/pull mechanism, such as pull wire, may be utilized to deform thehypotube extensions. Alternatively, a pressure or vacuum channel may beused. An array of hypotubes and/or hypotube extension electrodesoptionally may be deployed via a single deployment mechanism.

With reference to FIGS. 18A-D, alternative embodiments of the ITEV PEFsystem 350 are described. In FIGS. 18A-D, the guide block(s) 362 havebeen replaced with alternative deployment mechanisms comprising at leastone expandable member, such as an inflatable balloon 366. Furthermore,the hypotube 358 has been replaced with a stent-like element 370 havingthe extensions 359. As will be apparent, the balloon(s) 366alternatively may be used in combination with the hypotube 358, and/orthe stent-like element 370 alternatively may be used in combination withthe guide block(s) 362.

As with the hypotube 358, the stent-like element 370 may be completelyconductive and may serve as a unitary electrode. Alternatively, thestent-like element 370 may be fabricated from a relatively insulatingmaterial with electrode contacts that are etched or deposited onto theelement and/or its extensions. A variety of electrode configurations maybe provided. Furthermore, the multiple elements 370 (or a combination ofhypotubes 358 and elements 370) may be provided. In addition or as analternative to the deployment mechanisms illustrated in FIG. 18, theextensions 359 may be deployed via other deployment mechanisms, such aspush/pull mechanisms (e.g., a pull wire) or a pressure/vacuum channel.

As seen in the embodiment of FIGS. 18A and 18B, the system 350 may bepositioned at a treatment site, and the balloon 366 coupled to the innershaft 360 may be inflated into contact with the vessel wall. As seen inFIG. 18A, the inflated balloon 366 centers the system 350 within thevessel and provides a tapered guide path that provides a smoothtransition for deformation of the extensions 359 of the stent-likeelement 370 during ITEV placement of the extension electrodes. As seenin FIG. 18B, the outer shaft 356 may be advanced relative to the innershaft 360 such that the extensions 359 begin to deform about the balloonand are directed radially outward. This deformation optionally may beassisted via additional deployment mechanisms, such as pull-wires, tobegin deformation of the extensions 359. Continued advancement of theouter shaft 356 relative to the inner shaft causes the extensions 359 topierce the vessel wall so that the ends of the extension electrodes 359are positioned extravascularly via an ITEV approach.

As seen in FIG. 18C, the stent-like element 370 may compriselongitudinally spaced extensions 359 a and 359 b to providelongitudinally spaced bipolar electrode pairs. In FIG. 18C, the innershaft 360 comprises distal and proximal expandable elements,illustratively a distal balloon 366 a and a proximal balloon 366 b. Thestent-like element 370 is positioned between the proximal and distalballoon, with the extensions 359 a and 359 b overlapping the distal andproximal balloons 366 a-b, respectively. This overlap obviates a needfor the outer shaft 356 shown in FIGS. 18A and 18B. ITEV placement ofthe extension electrodes 359 a-b is achieved by inflating balloons 366.

As seen in FIG. 18D, the stent-like element 370 with proximal and/ordistal extensions 359 may be positioned over an expandable element, suchas inflatable balloon 366. The expandable element 370 may be coupled tothe shaft 360 proximally and/or distally (e.g., at a distal collar 368 aand at a proximal collar 368 b). At least one of the collars 368 a or368 b is slidingly coupled to the shaft 360 to facilitate expansion ofthe expandable element 370 during expansion of the balloon 366. As withthe embodiment of FIG. 18C, the positioning of the expandable element370 relative to the balloon 366 obviates a need for an outer shaft.Rather, ITEV placement of the extension electrodes is achieved byinflating the balloon 366.

Referring now to FIGS. 19A and 19B, an alternative ITEV PEF 400 systemis described comprising an expandable stent. The ITEV PEF system 400comprises a stent 402 having extensions 404 configured to pierce thewall of a patient's vasculature upon expansion of the stent. Theextensions 404 may be proximal and distal extensions that formlongitudinally spaced bipolar electrode pairs. Additionally, theextensions 404 can be electrically coupled to the PEF generator 50 andutilized as extravascular electrodes for delivery of PEF therapy.

As seen in FIG. 19A, a stent 402 may be delivered to an intravasculartreatment site, such as a site within renal artery RA, in a reducedprofile configuration. The stent 402 may, for example, be positioned ona delivery and deployment catheter, such as a balloon catheter 410,during advancement and deployment at the treatment site. The catheter410 may (temporarily) electrically couple the stent to the PEFgenerator. As seen in FIG. 19B, when the stent 402 is properlypositioned at the treatment site, it may be deployed to contact thevessel wall (e.g., via the deployment catheter) such that extensions 404penetrate the wall of the vessel. This accordingly positions theextension electrodes extravascularly via an ITEV approach. PEF therapythen may proceed, and upon completion the catheter 410 may be collapsedand removed from the patient.

The system 400 facilitates repeat PEF therapy at a later time. Forexample, by temporarily electrically re-coupling the catheter 410 orsome other electrical coupling element to the stent 402, the system 400can repeat PEF therapy as desired. When utilized to achieve renaldenervation, such repeat therapy may, for example, be repeated uponevidence of re-innervation of the renal(s).

Although preferred illustrative variations of the present invention aredescribed above, it will be apparent to those skilled in the art thatvarious changes and modifications may be made thereto without departingfrom the invention. For example, although the variations primarily havebeen described for use in combination with pulsed electric fields, itshould be understood that any other electric field may be delivered asdesired. It is intended in the appended claims to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

We claim:
 1. A method for pulsed electric field neuromodulation via anintra-to-extravascular approach, the method comprising: intravascularlyadvancing an electrode to a treatment site within vasculature of a humanpatient; passing a portion of the electrode through at least a portionof a wall of the vasculature to position the electrode at anextravascular location via an intra-to-extravascular approach; andextravascularly delivering a pulsed electric field via the electrode toinduce neuromodulation.
 2. The method of claim 1, whereinintravascularly advancing an electrode to a treatment site withinvasculature of a human patient further comprises intravascularly movingthe electrode to a treatment site within a renal artery of the patient.3. The method of claim 1, wherein intravascularly advancing an electrodeto a treatment site within vasculature of a human patient furthercomprises intravascularly moving an intravascular catheter having theelectrode to the treatment site within the vasculature of the patient.4. The method of claim 3, wherein passing a portion of the electrodethrough at least a portion of a wall of the vasculature to positioningthe electrode at an extravascular location via an intra-to-extravascularapproach further comprises expanding an expandable element of thecatheter.
 5. The method of claim 1, wherein intravascularly advancing anelectrode to a treatment site within vasculature of a human patientfurther comprises moving the electrode through an intravascular catheterpositioned at the treatment site.
 6. The method of claim 1, whereinextravascularly delivering a pulsed electric field to induceneuromodulation further comprises extravascularly applying the pulsedelectric field to modulate a neural fiber that contributes to renalfunction.
 7. The method of claim 6, wherein modulating a neural fiberthat contributes to renal function further comprises inducing, in theneural fiber, an effect chosen from the group consisting of irreversibleelectroporation, electrofusion, necrosis, apoptosis, gene expressionalteration, cytokine upregulation alteration, and combinations thereof.8. The method of claim 1 wherein passing a portion of the electrodethrough at least a portion of a wall of the vasculature to position theelectrode at an extravascular location via an intra-to-extravascularapproach further comprises piercing the wall of the vasculature, andadvancing the electrode through the wall piercing.
 9. The method ofclaim 8, wherein piercing the wall of the vasculature further comprisesforcing the electrode through the wall of the vasculature.
 10. Themethod of claim 1, wherein intravascularly advancing an electrode to atreatment site further comprises advancing at least one bipolarelectrode pair to the treatment site.
 11. The method of claim 10,wherein passing a portion of the electrode through at least a portion ofa wall of the vasculature to position the electrode at an extravascularlocation via an intra-to-extravascular approach further comprises movingthe bipolar electrode pair extravascularly, and wherein extravascularlydelivering a pulsed electric field further comprises extravascularlydelivering the pulsed electric field across the bipolar electrode pair.12. The method of claim 10, wherein passing a portion of the electrodethrough at least a portion of a wall of the vasculature to position theelectrode at an extravascular location via an intra-to-extravascularapproach further comprises positioning a first electrode of the bipolarelectrode pair at the extravascular location and positioning a secondelectrode of the bipolar electrode pair at an intravascular location.13. The method of claim 1 further comprising infusing an agent toenhance the neuromodulation.
 14. The method of claim 1 furthercomprising infusing an agent to protect non-target tissue.